Vascular grafting is performed clinically to repair or replace diseased coronary artery and peripheral vessels to restore normal blood flow patterns. Synthetic grafts composed of polymers such as Dacron and expanded polytetrafluoroethylene do not work well in small diameter (<6 mm) vessels. Such grafts exhibit low patency rates and fail, in large part, due to compliance mismatch. Compliance describes how the mechanical properties of a vascular graft change as a function of the internal hemodynamic pressure. Natural blood vessels display a complex non-linear 'J-shaped'stress-strain biomechanical behavior which is a function of extracellular matrix elastin and collagen nanofibers. Elastic fibers with straight conformation dominate the low elastic modulus at low levels of vessel distention. While collagen nanofibers with a wavy or helical orientation, with little resistance to expansion at lower values of vessel distention, dominate the high elastic modulus at higher levels of vessel distention as the nanofibers straighten. In addition to compliance, possession of a non-thrombogenic inner lining, biocompatibility and, after recipient cell ingrowth, vasoactivity is important for long term function of vascular grafts. The innovation in this proposal is design and manufacturing of composite nanofiber-based tissue-engineered vascular grafts (TEVGs) which mimic the potential implant site's arterial extracellular matrix microstructure and mechanical properties. In other words the grafts will be designed to match the compliance of each type of artery that requires replacement. Our preliminary data has demonstrated our ability to fabricate synthetic nanofibrous composite materials with overall mechanical properties matching those of a natural blood vessel (aorta) by employing a non-degradable elastin-like nanofiber and degradable collagen-like nanofibers. In this proposal these materials will be used in the construction of TEVGs mimicking the rabbit's carotid artery followed by evaluation in three specific aims. These aims include biomechanics and graft seeding with cells and in vitro assessment of remodeling profiles and retention of mechanical properties including compliance, burst strength and suture pull strength over time. Finally, cell-free TEVG designs will be assessed by vascular grafting in vivo. Patency, quantitative histology, mechanical properties and development of vasoactivity will be determined after one month post-implantation. Feasibility for progression to Phase II SBIR studies will be demonstrated by retention of biomaterial properties with e80% patency, the development of significantly better carotid-like vasoactivity after ingrowth of recipient cells and less anastomotic hyperplasia than controls (TEVGs without collagen-like microstructures) at explant. In Phase II we will propose large animal preclinical studies and other testing required for federal regulatory clearance for human trials. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is a leading cause of patient morbidity and mortality. Effective small diameter vascular grafts are an unmet clinical need. The potential impact of this project is design and production of effective composite nanofiber-based tissue-engineered vascular grafts for patients requiring small diameter artery repair or replacement. The potential world-wide market for vascular grafts is predicted to be 1,657,000 units valued at $2,588M by the year 2013. The simplicity, versatility, and scalability of our proposed approach will allow rapid clinical translation and market penetration.